1. Field of the Invention
The present invention relates to the field of methods for treating and preventing late-phase allergic reactions, such as late-phase cutaneous allergic reactions. The present invention also relates to the field of treatments for inflammatory diseases, allergic rhinitis, asthma, contact dermatitis, anaphylaxis, and urticaria. The present invention also relates to the field of pharmaceutical agents, as a pharmaceutical anti-allergy agent for treating a late phase allergic response in an animal is also provided.
2. Description of the Relevant Art
Prostaglandins (PGE) have historically been implicated in the pathogenesis of inflammation. This group of chemical mediators are known to have a variety of diverse functions, including the modulation of inflammatory cells. For example, the E series of prostaglandins inhibits the activity of many inflammatory cells. PGE prevents the synthesis of cytokines by monocytes and blocks the release of mediators from polymorphonuclear cells (PMN) and basophils. They also affect the function of lymphocytes.
PGE has been shown to have many anti-inflammatory and immunomodulatory effects. PGE is known to inhibits the activation of neutrophils, basophils, and monocytes. It also blocks the proliferation of lymphocytes and the expression of IL 2 receptors. PGE is also a strong smooth muscle relaxant and induces bronchodilatation in vivo. The immunomodulatory effect of PGE has been demonstrated by the increased survival of renal allografts in transplant recipients.
Theories surrounding the current understanding of the pathophysiology of allergic diseases has changed significantly in recent years. Initially considered as a disorder of mast cells, it is now increasingly recognized as a chronic inflammatory disease. The involvement of eosinophils, lymphocytes, basophils, monocytes/macrophages and neutrophils has also been recently appreciated.
It is believed that cytokines and interleukins released by activated lymphocytes and macrophages attract other inflammatory cells. "Mediators" of inflammation, of which there are many, are released by eosinophils, basophils and other effector cells, and induce a chronic inflammation that is reminiscent of chronic asthma and other allergic disorders.
An important development in the area of allergic diseases has been the recognition of a "late-phase" allergic reaction that follows approximately 2-12 hours after an immediate "early-phase" allergic reaction, which is separately characterizable both in sequence of onset and differences in appearance and general severity of symptoms. Morphologic studies have demonstrated the infiltration of eosinophils, basophils, neutrophils and activated lymphocytes during a "late-phase" allergic reaction.
The significance of the late-phase reaction has been substantiated by studies using pharmacologic modulators. Drugs that inhibit the late-phase reaction (e.g., corticosteroids, cromolyn sodium) have been observed to induce clinical remission by reducing inflammation and bronchial hypereactivity. In contrast, drugs that are effective only for the inhibition of an immediate (or "early-phase") allergic reaction only, do not appear to affect the course of the chronic disease.
Misoprostol, a PGE analogue, has been shown to have similar immunomodulatory effects as the parent compound, prostaglandin E, in some experiments. Molecularly, misoprostol consists of four individually characterized isomers. Its molecular structure includes an =OH on carbon 9 and an alpha-OH on carbon 11 of the cyclopentane ring of the structure. The action of misoprostol as a gastro-protective agent in experimental animals has been observed by several investigators. Because of this particular protective action, misoprostol has been approved for use in the prevention of gastric mucosal ulcers associated with nonsteroidal anti-inflammatory drugs (NSAIDS) in high risk patients. However, the cellular mechanism by which misoprostol provides this gastro-protective action remains uncertain.
Misoprostol has been described as having an action profile similar to that of the corticosteroids. Misoprostol has also been characterized as being essentially free of therapeutic activity other than in the gastrointestinal tract. This particular agent may not be prescribed for administration to reproductively active women because of its known deleterious physiological effects during pregnancy. Administered orally, misoprostol is also known to cause diarrhea in a significant percentage of patients. Misoprostol is also known by the name CYTOTEC.RTM..
Misoprostol has not been investigated or described as having anti-allergy activity. However, studies presented herein by the inventors demonstrate that according to the inventive method described by the inventors, misoprostol may be employed in inhibiting that condition characterized during the "late-phase" (i.e., 2-12 hours after initial allergen exposure) of a cutaneous allergic reaction. These results are most surprising and unexpected, as misoprostol has such a short half-life and because the "late phase" of an allergic reaction until 2 to 12 hours after exposure to an allergen.
Misoprostol, at concentrations of 10.sup.-8 to 10.sup.-4 M, has also been found by the present inventors to inhibit histamine release from basophils in vitro. Previous studies with PGE have demonstrated an inhibitory effect on basophils at similar concentration.
Cytokines and interleukins play an important role in the induction of inflammation. Activation of T cells and macrophages by foreign antigens leads to the synthesis of various cytokines including the interleukins (IL 1-IL 11), CSFs (colony stimulating factor), TNF (tumor necrosis factor) and the interferons. The interleukins and cytokines have diverse biological effects. For example, IL 1 activates T cells, B cells, granulocytes and many other tissue cells. In addition, many cytokines are known to have a potent pro-allergic action in vivo.
The inventors have shown that IL3 and GM-CSF activate basophils and cause histamine release. The present inventors have also described a group of cytokines called histamine releasing factors (HRF). HRF has also been shown to correlate with the severity of bronchial asthma. Immunotherapy has been observed to cause a reduction in the synthesis of HRF. Some studies have demonstrated the inhibition of IL 5 activity (by administering anti-IL 5 antibody) will prevent eosinophilic inflammation.
The present inventors have recently described a group of cytokines called histamine release inhibitory (HRIF) that block cytokine-induced mediator release from basophils. One species of HRIF appears to be identical to IL 8. IL 8 has been shown to inhibit histamine release by HRF, CTAPIII and IL3. The present inventors postulate that given the results presented herein, a network of cytokines may be functioning to modulate the function of basophils.
An important pro-inflammatory mechanism of action of cytokines is their induction of adhesion molecules on endothelium and leukocytes. For example, IL 1, TNF, GM-CSF and IFN-gamma are strong inducers of the expression of adhesion molecules. Endothelial cells also express a series of adhesion molecules, including intercellular adhesion molecules (ICAM) 1 and 2, endothelial leukocyte adhesion molecules (ELAM) 1, endoCAM (CD31), vascular cell adhesion molecule (VCAM) 1, and GMP 140. These molecules are instrumental in directing the traffic of the inflammatory cell to the target tissue.
Granulocytes, lymphocytes and monocytes also express a series of adhesion molecules that are ligands/receptors for endothelial cell counterparts. The migration of lymphocytes is mediated by a number of homing receptors such as CD44 (hermes antigen), leukocyte adhesion molecule (LAM)1, and integrins (e.g., VLA 4,5, and 6, LFA-1 (CD11a/CD18)).
The integrins are one of a group of molecules involved in granulocyte emigration from the blood vessels. Other molecules that have this activity include LFA-1 (CD11a/CD18), MAC-1 (CD11b/CD18), gp 150/95 (CD11c/CD18), ICAM-1, GMP 140 and others. Leukocyte adhesion molecules are unregulated by cytokines such as IL 1, TNF, IFN-gamma and GM-CSF, and inflammatory mediators such as platelet activating factor (PAF). The effect of prostaglandins and misoprostol on the expression of adhesion molecules on endothelium and inflammatory cells is unknown.
An allergy is generally recognized as a hypersensitivity to the exposure of a particular agent or substance, termed an "allergen." Allergies may be classified as immediate and delayed, and include atopy, serum sickness, allergic drug reactions, contact dermatitis, urticaria, asthma, allergic rhinitis and anaphylactic shock. Allergies are principally manifest in the gastrointestinal tract, the skin, the respiratory tract, and the cardiovascular system (e.g. during anaphylactic shock). Contact dermatitis is an example of a type IV hypersensitive reaction of the skin produced by contact with a chemical substance having the properties of an antigen or a hapten.
Typically, an allergic reaction may be divided into an early phase and a late phase. An early-phase allergic reaction typically takes place within 15-30 minutes after exposure to an allergen. Typical symptoms are shortness of breath, bronchospasm, soft tissue swelling, edema, hypotension, itching, redness of the skin, wheezing, nausea, vomiting, diarrhea, cramps, and, in some cases, shock. Symptoms usually resolve spontaneously after treatment. Mediators of early allergic reaction by way of example include histamine, leukotrienes, platelet activating factor, and kinins. These mediators are released primarily by mast cells and basophils. The treatment of the early phase reaction typically includes use of antihistamines, cromolyn sodium and beta-adrenergic drugs. The late phase reaction is a late phase sequela of the early reaction, and takes place 3-12 hours later. It is caused by mediators secreted by many inflammatory cells including eosinophils, basophils, monocytes, lymphocytes, and neutrophils. This type of reaction is clinically more relevant, since it correlates better with the clinical severity of the diseased state, such as with the disease, asthma. Late-phase allergic reactions are also generally more painful than early-phase allergic reactions. Treatment for these maladies typically includes administration of corticosteroids and cromolyn sodium.
Asthma is also a form of allergic reaction which is characterized by the release of histamine and other inflammatory mediators in the pulmonary tissue. Asthma typically results in impaired breathing capacity. One particular example of a delayed or "late-phase" (terms used interchangeably in the present invention) allergic reaction is observed in the cutaneous skin allergic response to the antigen of dust mites.
Corticosteroids are highly effective drugs for treatment of asthma and other allergic disease, but they have a multitude of serious side effects which include osteoporosis, obesity hypertension, cataracts, gastric ulcer reactivation of tuberculosis, delayed bone healing, predisposition to infection and adrenal insufficiency.
A method or agent for inhibiting late-phase allergic reactions, particularly late-phase allergic cutaneous reactions and respiratory related allergic maladies, without corticosteroids, would provide an improvement in the clinical management of late-phase allergic reactions.